Every day, a child is born in the Netherlands with a metabolic disease. Sadly, a quarter of these children do not reach adulthood because many metabolic diseases are (still) untreatable. This dissertation focuses on developing gene correction therapies, with a particular focus on the liver鈥攖he body鈥檚 central metabolic organ. To test these therapies, we used liver organoids: miniature liver models grown from patient tissue.
As a treatment approach, we investigated prime editing, a promising genetic technology designed to correct DNA mutations. We successfully applied this technique in patient-derived organoids. Since optimizing prime editing for different mutations proved challenging, we developed fluoPEER鈥攁 fluorescent reporter system that immediately shows whether prime editing is effective. This tool allows us to fine-tune prime editing for newly identified mutations. However, prime editing cannot target the portion of our DNA in mitochondria. To address this, we explored a new technique called DdCBE and successfully corrected mitochondrial mutations as well.
To test therapies in patient liver cells, we compared various existing liver models. We found that our original liver organoids primarily mimicked bile duct cells. Therefore, we developed a new liver organoid model called HeLLO, which more closely resembles actual liver cells. This model enables us to test gene therapies and predict drug-induced liver toxicity. We've filed a patent and created a business plan for our start-up, helloR&D.
Finally, we developed delivery methods and drafted a roadmap to bring gene editing therapies to the clinic, addressing technical, legal, and financial hurdles.
- Start date and time
- End date and time
- Location
- PhD candidate
- I.P. Joore
- Dissertation
- Gene correction on a roll
- PhD supervisor(s)
- prof. S.A. Fuchs
- prof. dr. E.E.S. Nieuwenhuis
- prof. dr. J.C. Clevers
- More information